Baseline GABA+ levels in areas associated with sensorimotor control predict initial and long-term motor learning progress.

Synaptic plasticity relies on the balance between excitation and inhibition in the brain. As the primary inhibitory and excitatory neurotransmitters, gamma-aminobutyric acid (GABA) and glutamate (Glu), play critical roles in synaptic plasticity and learning. However, the role of these neurometabolites in motor learning is still unclear. Furthermore, it remains to be investigated which neurometabolite levels from the regions composing the sensorimotor network predict future learning outcome. Here, we studied the role of baseline neurometabolite levels in four task-related brain areas during different stages of motor skill learning under two different feedback (FB) conditions. Fifty-one healthy participants were trained on a bimanual motor task over 5 days while receiving either concurrent augmented visual FB (CA-VFB group, N = 25) or terminal intrinsic visual FB (TA-VFB group, N = 26) of their performance. Additionally, MRS-measured baseline GABA+ (GABA + macromolecules) and Glx (Glu + glutamine) levels were measured in the primary motor cortex (M1), primary somatosensory cortex (S1), dorsolateral prefrontal cortex (DLPFC), and medial temporal cortex (MT/V5). Behaviorally, our results revealed that the CA-VFB group outperformed the TA-VFB group during task performance in the presence of augmented VFB, while the TA-VFB group outperformed the CA-VFB group in the absence of augmented FB. Moreover, baseline M1 GABA+ levels positively predicted and DLPFC GABA+ levels negatively predicted both initial and long-term motor learning progress in the TA-VFB group. In contrast, baseline S1 GABA+ levels positively predicted initial and long-term motor learning progress in the CA-VFB group. Glx levels did not predict learning progress. Together, these findings suggest that baseline GABA+ levels predict motor learning capability, yet depending on the FB training conditions afforded to the participants.

Neural compensation in manifest neurodegeneration: systems neuroscience evidence from social cognition in frontotemporal dementia.

BACKGROUND: It has been argued that symptom onset in neurodegeneration reflects the overload of compensatory mechanisms. The present study aimed to investigate whether neural functional compensation can be observed in the manifest neurodegenerative disease stage, by focusing on a core deficit in frontotemporal dementia, i.e. social cognition, and by combining psychophysical assessment, structural MRI and functional MRI with multidimensional neural markers that allow quantification of neural computations. METHODS: Nineteen patients with clinically manifest behavioral variant frontotemporal dementia (bvFTD) and 20 controls performed facial expression recognition tasks in the MRI-scanner and offline. Group differences in grey matter volume, neural response amplitude and neural patterns were assessed via a combination of voxel-wise whole-brain, searchlight, and ROI-analyses and these measures were correlated with psychophysical measures of emotion, valence and arousal ratings. RESULTS: Significant group effects were observed only outside task-relevant regions, converging in the caudate nucleus. This area showed a diagnostic neural pattern as well as hyperactivation and stronger neural representation of facial expressions in the bvFTD sample. Furthermore, response amplitude was associated with behavioral arousal ratings. CONCLUSIONS: The combined findings reveal converging support for compensatory processes in clinically manifest neurodegeneration, complementing accounts that clinical onset synchronizes with the breakdown of compensatory processes. Furthermore, active compensation may proceed along nodes in intrinsically connected networks, rather than along the more task-specific networks. The findings underscore the potential of distributed multidimensional functional neural characteristics that may provide a novel class of biomarkers with both diagnostic and therapeutic implications, including biomarkers for clinical trials.

A paleo-neurologic investigation of the social brain hypothesis in frontotemporal dementia.

The social brain hypothesis posits that a disproportionate encephalization in primates enabled to adapt behavior to a social context. Also, it has been proposed that phylogenetically recent brain areas are disproportionally affected by neurodegeneration. Using structural and functional magnetic resonance imaging, the present study investigates brain-behavior associations and neural integrity of hyperspecialized and domain-general cortical social brain areas in behavioral variant frontotemporal dementia (bvFTD). The results revealed that both structure and function of hyperspecialized social areas in the middle portion of the superior temporal sulcus (STS) are compromised in bvFTD, while no deterioration was observed in domain general social areas in the posterior STS. While the structural findings adhered to an anterior-posterior gradient, the functional group differences only occurred in the hyperspecialized locations. Activity in specialized regions was associated with structural integrity of the amygdala and with social deficits in bvFTD. In conclusion, the results are in line with the paleo-neurology hypothesis positing that neurodegeneration primarily hits cortical areas showing increased specialization, but also with the compatible alternative explanation that anterior STS regions degenerate earlier, based on stronger connections to and trans-neuronal spreading from regions affected early in bvFTD.

Long term fMRI adaptation depends on adapter response in face-selective cortex.

Repetition suppression (RS) reflects a neural attenuation during repeated stimulation. We used fMRI and the subsequent memory paradigm to test the predictive coding hypothesis for RS during visual memory processing by investigating the interaction between RS and differences due to memory in category-selective cortex (FFA, pSTS, PPA, and RSC). Fifty-six participants encoded face and house stimuli twice, followed by an immediate and delayed (48 h) recognition memory assessment. Linear Mixed Model analyses with repetition, subsequent recognition performance, and their interaction as fixed effects revealed that absolute RS during encoding interacts with probability of future remembrance in face-selective cortex. This effect was not observed for relative RS, i.e. when controlled for adapter-response. The findings also reveal an association between adapter response and RS, both for short and long term (48h) intervals, after controlling for the mathematical dependence between both measures. These combined findings are challenging for predictive coding models of visual memory and are more compatible with adapter-related and familiarity accounts.

Cortical thinning and altered functional brain coherence in survivors of childhood sarcoma.

High-dose chemotherapy is increasingly evidenced to be neurotoxic and result in long-term neurocognitive sequelae. However, research investigating grey matter alterations in childhood cancer patients remains limited. As childhood sarcoma patients receive high-dose chemotherapy, we aimed to investigate cortical brain alterations in adult survivors. We analyzed high-resolution structural (T1-weighted) MRI and resting-state functional MRI (rsfMRI), to derive structural and functional cortical information in survivors of childhood sarcoma, treated with high-dose intravenous chemotherapy (n = 33). These scans were compared to age- and gender- matched controls (n = 34). Cortical volume and thickness were investigated using voxel-based morphometry and vertex-wise surface-based morphometry. Brain regions showing significant group differences in volume or thickness were implemented as seeds of interest to estimate their resting state co-activity with other areas (i.e. functional coherence). We explored whether structural measures were associated with potential risk factors, such as age at diagnosis, and cumulative doses of chemotherapeutic agents (methotrexate, ifosfamide). Finally, we investigated the link between functional regional strength, neurocognitive assessments and daily life complaints. In patients relative to controls we observed lower grey matter volumes in cerebellar and frontal areas, as well as frontal cortical thinning. Cerebellar volume and orbitofrontal thickness appeared dose- and age-related, respectively. Cortical thickness of the parahippocampal area appeared lower, only if the group comparison was not adjusted for depression. This region specifically showed lower functional coherence, which was associated with lower processing speed. This study suggests cortical thinning as well as decreased functional coherence in survivors of childhood sarcoma, which could be important for both long-term attentional functioning and emotional distress in daily life. Frontal areas might be specifically vulnerable during adolescence.

Network level characteristics in the emotion recognition network after unilateral temporal lobe surgery.

The human amygdala is considered a key region for successful emotion recognition. We recently reported that temporal lobe surgery (TLS), including resection of the amygdala, does not affect emotion recognition performance (Journal of Neuroscience, 2018, 38, 9263). In the present study, we investigate the neural basis of this preserved function at the network level. We use generalized psychophysiological interaction and graph theory indices to investigate network level characteristics of the emotion recognition network in TLS patients and healthy controls. Based on conflicting emotion processing theories, we anticipated two possible outcomes: a substantial increase of the non-amygdalar connections of the emotion recognition network to compensate functionally for the loss of the amygdala, in line with basic emotion theory versus only minor changes in network level properties as predicted by psychological construction theory. We defined the emotion recognition network in the total sample and investigated group differences on five network level indices (i.e. characteristic path length, global efficiency, clustering coefficient, local efficiency and small-worldness). The results did not reveal a significant increase in the left or right temporal lobectomy group (compared to the control group) in any of the graph measures, indicating that preserved behavioural emotion recognition in TLS is not associated with a massive connectivity increase between non-amygdalar nodes at network level. We conclude that the emotion recognition network is robust and functionally able to compensate for structural damage without substantial global reorganization, in line with a psychological construction theory.

Qualitative and quantitative analysis of diffusion-weighted brain MR imaging in comatose survivors after cardiac arrest.

PURPOSE: The aim of this study is to compare a qualitative and a quantitative assessment of brain diffusion-weighted imaging (DWI) in predicting outcome of comatose patients after cardiac arrest (CA). METHODS: Two observers used a scoring template to analyze the DWI of 75 patients. A total of 13 regions were scored from 0 to 3 (0 = normal, 1 = probably normal, 2 = probably abnormal, 3 = definitely abnormal). The total cerebral cortex (TCC), the total deep grey nuclei (TDGN), the total brain stem, the total cerebellum, and the total brain score were calculated. Intra- and inter-observer variability were tested. The mean whole brain apparent diffusion coefficient (ADC) values and percentage of voxels below a specific ADC value cut-off were calculated. The data were correlated with clinical outcome (cerebral performance category score after 180 days, dichotomized in a score 1-2 with favorable outcome and score 3-5 with unfavorable outcome) using ROC analysis. RESULTS: Intra-observer variability was excellent for the TCC score (ICC 0.95 and 0.86) and the TDGN score (ICC 0.89 and 0.75). Inter-observer variability was good to excellent for total cerebral cortex score and total deep grey nuclei score in both the first (ICC 0.78 and 0.69) and third (ICC 0.86 and 0.83) image assessment. TCC and TDGN score show the best correlation with clinical outcome (highest AUC values 0.87 and 0.87). Quantitative parameters did not show good correlation with clinical outcome (AUC values 0.57 and 0.60). CONCLUSION: A qualitative assessment of brain DWI using a scoring template provides useful data regarding patient outcome while quantitative data appeared less reliable.

Age-dependent brain volume and neuropsychological changes after chemotherapy in breast cancer patients.

This study investigated volumetric brain changes and cognitive performance in premenopausal and postmenopausal patients treated for early-stage breast cancer. Participants underwent elaborate neurocognitive assessments (neuropsychological testing, cognitive failure questionnaire, and high-resolution T1-weighted structural MRI) before and after chemotherapy. Volumetric brain changes were estimated, using longitudinal deformation-based morphometry, and correlated with cognitive changes. In total, 180 women participated in this study, of whom 72 patients with breast cancer had received adjuvant chemotherapy (C+), 49 patients did not receive chemotherapy (C-), and 59 healthy controls (HC). The population was categorized into two age groups: A young group who were premenopausal and younger than 52 years at baseline (n = 55C+/32C-/41HC), and an older group who were postmenopausal and older than 60 years (n = 17C+/17C-/18HC). Cognitive impairment occurred after chemotherapy in both young and older patients, although older patients showed more decline in processing speed (Trail making test b). White matter volume expansion was observed after chemotherapy, only significantly present in the younger subgroup of patients. In patients not treated with chemotherapy, diffuse gray and white matter volume reduction was observed. Less white matter expansion concurred with more cognitive decline (r > .349, p < .05). In conclusion, we found age-dependent cognitive decline and white matter volume changes in patients with breast cancer after chemotherapy, which could possibly be linked to neuroinflammatory processes. White matter expansion after chemotherapy, more pronounced in premenopausal patients, correlated with less cognitive decline. This suggests such expansion to be age-dependent, possibly caused by a protective response in the younger brain to chemotherapy-induced neurotoxicity.

The functional neuroanatomy of multitasking: combining dual tasking with a short term memory task.

Insight into the neural architecture of multitasking is crucial when investigating the pathophysiology of multitasking deficits in clinical populations. Presently, little is known about how the brain combines dual-tasking with a concurrent short-term memory task, despite the relevance of this mental operation in daily life and the frequency of complaints related to this process, in disease. In this study we aimed to examine how the brain responds when a memory task is added to dual-tasking. Thirty-three right-handed healthy volunteers (20 females, mean age 39.9 ± 5.8) were examined with functional brain imaging (fMRI). The paradigm consisted of two cross-modal single tasks (a visual and auditory temporal same-different task with short delay), a dual-task combining both single tasks simultaneously and a multi-task condition, combining the dual-task with an additional short-term memory task (temporal same-different visual task with long delay). Dual-tasking compared to both individual visual and auditory single tasks activated a predominantly right-sided fronto-parietal network and the cerebellum. When adding the additional short-term memory task, a larger and more bilateral frontoparietal network was recruited. We found enhanced activity during multitasking in components of the network that were already involved in dual-tasking, suggesting increased working memory demands, as well as recruitment of multitask-specific components including areas that are likely to be involved in online holding of visual stimuli in short-term memory such as occipito-temporal cortex. These results confirm concurrent neural processing of a visual short-term memory task during dual-tasking and provide evidence for an effective fMRI multitasking paradigm.

Does somatosensory discrimination activate different brain areas in children with unilateral cerebral palsy compared to typically developing children? An fMRI study.

Aside from motor impairment, many children with unilateral cerebral palsy (CP) experience altered tactile, proprioceptive, and kinesthetic awareness. Sensory deficits are addressed in rehabilitation programs, which include somatosensory discrimination exercises. In contrast to adult stroke patients, data on brain activation, occurring during somatosensory discrimination exercises, are lacking in CP children. Therefore, this study investigated brain activation with functional magnetic resonance imaging (fMRI) during passively guided somatosensory discrimination exercises in 18 typically developing children (TD) (age, M=14 ± 1.92 years; 11 girls) and 16 CP children (age, M=15 ± 2.54 years; 8 girls). The demographic variables between both groups were not statistically different. An fMRI compatible robot guided the right index finger and performed pairs of unfamiliar geometric shapes in the air, which were judged on their equality. The control condition comprised discrimination of music fragments. Both groups exhibited significant activation (FDR, p<.05) in frontoparietal, temporal, cerebellar areas, and insula, similar to studies in adults. The frontal areas encompassed ventral premotor areas, left postcentral gyrus, and precentral gyrus; additional supplementary motor area (SMA proper) activation in TD; as well as dorsal premotor, and parietal operculum recruitment in CP. On uncorrected level, p<.001, TD children revealed more left frontal lobe, and right cerebellum activation, compared to CP children. Conversely, CP children activated the left dorsal cingulate gyrus to a greater extent than TD children. These data provide incentives to investigate the effect of somatosensory discrimination during rehabilitation in CP, on clinical outcome and brain plasticity.

How does brain activation differ in children with unilateral cerebral palsy compared to typically developing children, during active and passive movements, and tactile stimulation? An fMRI study.

The aim of the functional magnetic resonance imaging (fMRI) study was to investigate brain activation associated with active and passive movements, and tactile stimulation in 17 children with right-sided unilateral cerebral palsy (CP), compared to 19 typically developing children (TD). The active movements consisted of repetitive opening and closing of the hand. For passive movements, an MRI-compatible robot moved the finger up and down. Tactile stimulation was provided by manually stroking the dorsal surface of the hand with a sponge cotton cloth. In both groups, contralateral primary sensorimotor cortex activation (SM1) was seen for all tasks, as well as additional contralateral primary somatosensory cortex (S1) activation for passive movements. Ipsilateral cerebellar activity was observed in TD children during all tasks, but only during active movements in CP children. Of interest was additional ipsilateral SM1 recruitment in CP during active movements as well as ipsilateral S1 activation during passive movements and tactile stimulation. Another interesting new finding was the contralateral cerebellum activation in both groups during different tasks, also in cerebellar areas not primarily linked to the sensorimotor network. Active movements elicited significantly more brain activation in CP compared to TD children. In both groups, active movements displayed significantly more brain activation compared to passive movements and tactile stimulation.

Frontoparietal involvement in passively guided shape and length discrimination: a comparison between subcortical stroke patients and healthy controls.

Fifty to 85 % of patients with sensorimotor hemiparesis following stroke encounter impaired tactile processing and proprioception. Sensory feedback is, however, paramount for motor recovery. Sensory feedback through passively guided somatosensory discrimination exercises has been used in therapy, but so far, no studies have investigated which brain areas are involved in this process. Therefore, we performed a study with functional magnetic resonance imaging (fMRI) to examine brain areas related to discriminating passively guided shape and length discrimination in stroke patients and evaluate whether they differed from healthy age-matched controls. Eight subcortical stroke patients discriminated different shapes or length based on passive finger movements provided by an fMRI compatible robot. The data were contrasted to a control condition whereby patients discriminated music fragments. Passively guided somatosensory discrimination versus music discrimination elicited activation in similar frontoparietal areas in stroke patients compared to the healthy control group. Still, patients had increased activation in the right angular gyrus, left superior lingual gyrus, and right cerebellar lobule VI compared to healthy volunteers. Conversely, healthy volunteers activated the right precentral gyrus to a greater extent than patients. In both groups, shape discrimination resulted in anterior intraparietal sulcus and premotor activation, while length discrimination elicited a more medially located parietal activation with mainly right-sided premotor activity. The current study is a first step in clarifying brain activations during passively guided shape and length discrimination in subcortical stroke patients. Research into the effects of the use of sensory discrimination exercises on brain reorganization and brain plasticity is encouraged.

Hemispheric asymmetries in goal-directed hand movements are independent of hand preference.

Asymmetries in the kinematics and neural substrates of voluntary right and left eye-hand coordinated movements have been accredited to differential hemispheric specialization. An alternative explanation for between-hand movement differences could result from hand preference related effects. To test both assumptions, an experiment was conducted with left- and right-handers performing goal-directed movements with either hand paced by a metronome. Spatiotemporal accuracy was comparable between hands, whereas hand peak velocity was reached earlier when moving with the left compared to the right hand. The underlying brain activation patterns showed that both left- and right-handers activated more areas involved in visuomotor attention and saccadic control when using their left compared to the right hand. Altogether, these results confirm a unique perceptuomotor processing specialization of the left brain/right hand system that is independent of hand preference.

Hemispheric asymmetries in eye-hand coordination.

Manual asymmetries in limb kinematics and eye-hand coordination have usually been attributed to differences in online processing capabilities between the left and the right cerebral hemisphere. In the present fMRI experiment, we examined in right handers the brain areas involved in eye-hand coordination with either the left or the right hand. Although temporal and spatial accuracy was equal for left- and right-hand movements, manual asymmetries were found in behavioral and neurophysiologic data, suggesting an asymmetric mode of control for left vs. right eye-hand coordination. For left eye-hand coordination, peak velocity and saccade completion occurred earlier than for the contralateral movements, suggesting that there was more time needed for homing-in on the target. When using the right hand, there was more activation in occipital areas. This might indicate a more intense visual processing or visualization of the target locations. When using the left hand, there was more activation in sensorimotor areas, frontal areas and cerebellum. This might point toward more processing effort. Left-hand movements may be considered as more difficult than right-hand movements by right-handed participants. Alternatively and more likely, these findings might reflect a difference in attention or resources attributed to different aspects of the tasks because of the different functional specializations of both hand/hemisphere systems.

Passive somatosensory discrimination tasks in healthy volunteers: differential networks involved in familiar versus unfamiliar shape and length discrimination.

Somatosensory discrimination of unseen objects relies on processing of proprioceptive and tactile information to detect spatial features, such as shape or length, as acquired by exploratory finger movements. This ability can be impaired after stroke, because of somatosensory-motor deficits. Passive somatosensory discrimination tasks are therefore used in therapy to improve motor function. Whereas the neural correlates of active discrimination have been addressed repeatedly, little is known about the neural networks activated during passive discrimination of somatosensory information. In the present study, we applied functional magnetic resonance imaging (fMRI) while the right index finger of ten healthy subjects was passively moved along various shapes and lengths by an fMRI compatible robot. Comparing discriminating versus non-discriminating passive movements, we identified a bilateral parieto-frontal network, including the precuneus, superior parietal gyrus, rostral intraparietal sulcus, and supramarginal gyrus as well as the supplementary motor area (SMA), dorsal premotor (PMd), and ventral premotor (PMv) areas. Additionally, we compared the discrimination of different spatial features, i.e., discrimination of length versus familiar (rectangles or triangles) and unfamiliar geometric shapes (arbitrary quadrilaterals). Length discrimination activated mainly medially located superior parietal and PMd circuits whereas discrimination of familiar geometric shapes activated more laterally located inferior parietal and PMv regions. These differential parieto-frontal circuits provide new insights into the neural basis of extracting spatial features from somatosensory input and suggest that different passive discrimination tasks could be used for lesion-specific training following stroke.

Simultaneous electroencephalographic recording and functional magnetic resonance imaging during pentylenetetrazol-induced seizures in rat.

Truly simultaneous electroencephalogram (EEG) and functional magnetic resonance imaging (fMRI) were registered in curarized rats injected with convulsive doses of pentylenetetrazol (PTZ, 65 mg/kg, sc). Rigorous control of physiological parameters like body temperature and ventilation with control of blood gasses helped to avoid potential interference between systemic parameters, and central PTZ-induced blood oxygenation level-dependent (BOLD) changes. Simultaneous EEG/fMRI recordings demonstrated progressive epileptiform EEG discharges with concomitant BOLD changes, the latter gradually affecting most of the fore- and midbrain. Approximately 15 min after PTZ injection, the first BOLD contrast changes mainly occurred in neocortex, and coincided with the first minor EEG alterations. Most regions that displayed BOLD changes were regions with reportedly high GABA(A) receptor densities. Full-blown epileptiform discharges occurred on the EEG tracing, approximately 30 min after PTZ injection, and coincided with bilateral positive and/or negative BOLD contrast changes in cortical and subcortical regions. Behavioral observations demonstrated the first of several generalized clonic or clonic-tonic seizure episodes to occur also around this time. Approximately 90 min after injection, the electrographic paroxysms gradually decreased in amplitude and duration, whereas the BOLD signal changes still extended with alternating positive and negative traces, and spread to subcortical regions like caudate-putamen and globus pallidus.